The use of steroidal hormones is well known in modern clinical therapy. Examples of such hormones are corticoids, anabolic agents and various progesterones. However, the useful properties of these drugs are usually accompanied by undesirable activities or side effects. As a result, a variety of heterosteroids have been synthesized in the hope that the undesired properties could be separated from the desired effects.
Some success has indeed been observed in the case of 2-oxasteroids. [For reviews see R. Pappo, Intra-Science Chemistry Reports, 3, 105 (1969) and H. Singh et al., Prog. Med. Chem., 16, 35 (1979)]. For example in the heteroprogesterone series, 2-oxaprogesterone and its 17.alpha.-acetoxy analog are almost as active as progesterone and 17.alpha.-acetoxyprogesterone. In the cortisone series, 3-oxa-A-homo-11-hydrocortisone is at least as active as hydrocortisone and does not show salt retaining properties.
One of the most convenient methods of synthesizing 2-oxa-3-oxo-.DELTA..sup.4 -steroids (VI) is by reducing the corresponding 1-hydroxy-2-oxa-3-oxo-.DELTA..sup.4 -steroids (II) as outlined below. ##STR4## As shown, compounds of type II are hydroxy-lactones or lactols which are in equilibrium with the A-nor-1,2-seco aldehydo acid form IV. The latter is reduced, typically by sodium borohydride, to the corresponding 8-hydroxy acid V which readily dehydrates in turn yielding a lactone VI which is the desired 2-oxa-3-oxo-.DELTA..sup.4 -steroid. A similar approach is applicable to the 3-oxa-A-homo series.
Methods of synthesizing 1-hydroxy-2-oxa-3-oxo-.DELTA..sup.4 steroids (VI) are known in the prior art. Each of these methods suffers from a variety of shortcomings. For example, a method described in U.S. Pat. No. 3,128, 283 is a multistep process which involves the use of the expensive and toxic reagents osmium tetroxide and lead tetraacetate. Another approach, described in U.S. Pat. No. 3,644,342 involves the ozonolysis of the electron rich enolic double bond of 2-hydroxy-3-oxo-.DELTA..sup.1,4 steroids. However ozone is a very vigorous oxidizing agent and can well attack other olefinic sites and functional groups in the substrate. Furthermore the substrate itself needs to be synthesized from the corresponding 3-oxo-.DELTA..sup.4 -steroid. The method of Kocor et al. [Tetrahedron, 25, 4257 (1969)] involves the oxidation of a 3-oxo-.DELTA..sup.1,4 steroid with alkaline hydrogen peroxide and involves the intermediacy of the corresponding 1,2-epoxide. This method requires the prior synthesis and isolation of the 3-oxo-.DELTA..sup.1,4 steroid from the corresponding .DELTA..sup.4 -steroidal analog and thus introduces an additional step into the synthetic scheme.
A method has been reported [R. Hanna and G. Ourisson, Bull. Soc. Chim. Fra., 1945 (1961)] in which 3-oxosteroids saturated at the 4-carbon have been converted into the corresponding lactol, 1-hydroxy-2-oxa-3-oxo-steroid, either directly or via the intermediacy of the corresponding enol, 2-hydroxy-3-oxo-.DELTA..sup.1 -steroid, by the action of potassium t-butoxide in protic media (butanol-benzene solvent mixture) under a molecular oxygen atmosphere. However, it has been recently reported [R. J. Chorvat and R. Pappo, J. Org. Chem., 41, 2864 (1976)] that this method is unsuitable for the preparation of the unsaturated .DELTA..sup.4 -lactols of type II.